US Pharm. 2016;41(3):51-54.
ABSTRACT: Pain is the hallmark of fibromyalgia, which has sparked the theory that fibromyalgia is neurogenic in origin because it is associated with a central amplification of pain perception. Fibromyalgia is more often diagnosed in women, and patients who are younger upon diagnosis have a poorer prognosis and quality of life. The pain of fibromyalgia is hard to control. Possible mechanisms include central and autonomic nervous system dysfunction, as well as genetic and environmental factors. Treatment is difficult and should include both pharmacologic and nonpharmacologic options. There is no gold standard for treatment, and most patients use medications from various classes. The three FDA-approved medications are duloxetine, milnacipran, and pregabalin, with selection based on the patient’s overall characteristics.
Fibromyalgia syndrome, which was first described more than 100 years ago, is defined as chronic, widespread musculoskeletal pain characterized by both somatic and psychological symptoms.1,2 Aches, stiffness, soft-tissue tenderness, fatigue, sleep disturbances, anxiety, and cognitive dysfunction are among the symptoms of fibromyalgia.1,3 Fibromyalgia is commonly seen with other conditions, such as irritable bowel syndrome, low back pain, headaches, arthritis, and posttraumatic stress disorder.3,4 The first official diagnostic guidelines were published in 1990 by the American College of Rheumatology, followed by treatment guidelines published by the American Pain Society in 2005.2
In the United States, an estimated 2% to 8% of adults experience fibromyalgia, and studies indicate a global prevalence of 2.7%.1,4 Fibromyalgia is more common in persons older than 50 years (mostly ages 60-79 years) and in persons with lower socioeconomic status and education. Fibromyalgia is diagnosed three times more often in women than in men, with an incidence of 6.88 new cases of fibromyalgia per 1,000 in males and 11.28 new cases per 1,000 in females.1 Patients who are diagnosed at an earlier age (<39 years) have a poorer prognosis and quality of life. Overall, patients with fibromyalgia have a reduced quality of life and report having difficulties in everyday tasks, including bathing, lifting or carrying, and walking up stairs.2
Pathogenesis of Fibromyalgia
The fact that pain is the hallmark of fibromyalgia has caused experts to believe that the disorder is neurogenic in origin, as it is associated with a central amplification of pain perception characterized most prominently by hyperalgesia (increased response to painful stimuli) and allodynia (pain from stimuli not normally painful). Possible mechanisms include dysfunction of the central and autonomic nervous systems, genetic factors, and environmental factors, including infections and physical trauma. Studies have also linked fibromyalgia to sexual abuse, psychological stress, and deployment to war.2,3 Brain imaging has shown abnormalities in pain processing and reduced gray-matter volume in patients with fibromyalgia. These patients also exhibit polymorphisms to the serotonin receptor 2A region of chromosome 13 and the human leukocyte antigen region of chromosome 6, as well as abnormalities in catechol-O-methyltransferase.3
Diagnosis of Fibromyalgia
The diagnosis of fibromyalgia is subjective and is based on the patient’s complaint of pain and the accompanying symptoms previously mentioned. The pain is usually above or below the waist and bilateral. Patients whose pain lasts more than 3 months and who have 11 out of 18 tender-point sites are diagnosed with fibromyalgia syndrome.3,4 In 2010, the American College of Rheumatology published new diagnostic criteria, which were modified in 2011; currently, diagnosis is based on symptoms evaluated by the Widespread Pain Index and the Symptom Severity Scale. These evaluations have 83% sensitivity and 67% specificity.2
Treatment of Fibromyalgia
Because fibromyalgia is a chronic, complex condition with various comorbidities, treatment is difficult and should include both pharmacologic and nonpharmacologic options. There is no gold standard for treatment, and most patients use various medications from a number of classes to relieve their pain. Evidence-based guidelines recommend the use of at least two nonpharmacologic therapies combined with pharmacologic treatments for the management of fibromyalgia. Cognitive behavioral therapy (CBT), which is often used in patients with depression and anxiety, has been shown to be beneficial in fibromyalgia. Meta-analyses of randomized clinical trials have concluded that CBT reduces the fear and anxiety associated with fibromyalgia.3 Exercise has also been found to improve overall well-being, physical function, reports of pain, tenderness, and muscle strength. Complementary treatment options such as tai chi and acupuncture have also been used; however, efficacy data for acupuncture are lacking.2
As previously stated, fibromyalgia is a complex condition requiring different treatment modalities, and no single therapy is superior to the others with regard to efficacy. The various guidelines have different approaches to treatment; however, there is some homogeneity in the medications used. Currently, three medications are approved for the treatment of fibromyalgia syndrome. Pregabalin, which was the first drug to gain FDA approval for diabetic neuropathy, is an anticonvulsant and analgesic that works by binding to the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system.1,3 Numerous meta-analyses and clinical trials have concluded that pregabalin improved pain, fatigue, depressed mood, sleep disturbance, and health-related quality of life. The serotonin-norepinephrine reuptake inhibitors (SNRIs) duloxetine and milnacipran, which are the other two medications FDA-approved for fibromyalgia, are recommended by all clinical guidelines.1
In addition to these FDA-approved medications, a variety of drugs may be used off-label to treat the symptoms of fibromyalgia. The most notable of these is amitriptyline, a tricyclic antidepressant (TCA). Amitriptyline exerts its effect on pain modulation via serotonin and norepinephrine, and for many years it was the mainstay of therapy.5 In a systematic review evaluating the efficacy and acceptability of amitriptyline, duloxetine, and milnacipran, amitriptyline was found to improve pain, fatigue, and sleep and was concluded to be superior to duloxetine and milnacipran in those areas.1
Cyclobenzaprine, which is similar in structure to TCAs, has been shown to improve pain and sleep disturbances; however, many patients have reported adverse effects.2 Tramadol, a synthetic opioid receptor agonist with properties similar to those of SNRIs, inhibits the reuptake of biogenic amines—including serotonin and norepinephrine (similar to SNRI antidepressants)—and acts as a weak agonist at the mu-opioid receptor.4 Although some literature states that it may be used as first-line therapy, tramadol lacks FDA approval and is recommended as an alternative to duloxetine, milnacipran, or pregabalin.4 Nonsteroidal anti-inflammatory drugs have demonstrated benefits in combination with antidepressants or anticonvulsants, but they decrease the antidepressant action of selective serotonin reuptake inhibitors (SSRIs) and therefore are not used often.3
TABLE 1 summarizes the medications and lists common dosing and counseling points for pharmacists.
Pregabalin has effects on the release of glutamate, norepinephrine, and substance P that may contribute to the reduction of pain in patients with fibromyalgia.2 Pregabalin should be initiated at a dosage of 75 mg twice daily and titrated up to a target of 225 mg twice daily, depending on the patient’s creatinine clearance. Total daily doses of 300 mg, 450 mg, or 600 mg can reduce pain by more than 30% if the patient can tolerate the side effects of dizziness, somnolence, dry mouth, weight gain, and peripheral edema, especially at 600 mg.1,2
Duloxetine and milnacipran are SNRIs, but their exact mechanisms are not known.2 Initiating duloxetine at 30 mg once daily and titrating up after 1 week to 60 mg daily can help reduce the patient’s fibromyalgia pain, as well as anxiety and depression. The starting dosage of milnacipran is 12.5 mg daily, and the agent may be slowly titrated up to 50 mg twice daily. This regimen relieves the patient’s fibromyalgia pain, anxiety, and depression, but adjustments are needed in patients with renal insufficiency and those unable to tolerate the side effects.1,2
Treatment regimens for fibromyalgia have never been clinically compared. Since there are no direct clinical comparisons of the FDA-approved drugs, a systematic review was conducted to determine the similarities, advantages, and side effects of these medications.2 Compared with placebo, duloxetine, milnacipran, and pregabalin were superior in the treatment of fibromyalgia.1,2 Duloxetine was similar to placebo in the treatment of fatigue in fibromyalgia patients.2 Adverse effects between all of the FDA-approved medications were similar, except that headache and nausea were more common in duloxetine and milnacipran patients than in those receiving pregabalin.1,2
Off-label therapies, including amitriptyline, fluoxetine, gabapentin, cyclobenzaprine, and tramadol, have been shown to reduce patients’ fibromyalgia pain.1,2,5 In evaluations of two different dosages of amitriptyline, 25 mg improved patients’ pain, sleep disturbance, and fatigue, but the effectiveness of the 50-mg dosage was comparable to that of placebo, probably owing to high rates of adverse reactions.1,2 Adverse reactions in patients taking amitriptyline included dry mouth, somnolence, gastrointestinal disturbances, and weight gain.1,2 Cyclobenzaprine, which is similar in structure to TCAs, has been found helpful in fibromyalgia patients; 10 to 30 mg daily produced improvements in sleep and pain, but not in fatigue or tender-point pain.1,2 Gabapentin is similar to pregabalin, but limited studies have been done on its benefits for fibromyalgia.1,2 Dosages of 1,200 to 2,400 mg daily have resulted in a reduction in pain severity.1,2 Fluoxetine (SSRI) dosages of 10 mg to 80 mg daily have produced reductions in pain, depression, fatigue, and overall symptoms.1,2 A lower dosage was less effective, but its use in combination with other medications, such as amitriptyline, or with complementary/alternative methods, such as acupuncture, has provided relief.1 Finally, tramadol is a weak mu-opioid receptor agonist and weak serotonin and norepinephrine antagonist that has resulted in relief of fibromyalgia pain.1 Tramadol can be paired with acetaminophen to reduce pain even further.1
TCAs were the mainstay of therapy for fibromyalgia for many years. Amitriptyline, in particular, has been extensively studied for fibromyalgia treatment.1,2 Although the clinical trials of amitriptyline are old and involved small numbers of patients, a systematic review revealed that amitriptyline tended to show superiority over duloxetine, pregabalin, and milnacipran.2 Another meta-analysis found that amitriptyline was similar to the FDA-approved medications for the treatment of fibromyalgia.2 Given the flaws in previous studies, amitriptyline cannot be recommended as the gold standard for treatment of fibromyalgia until further studies are conducted.2
Fibromyalgia is a difficult disorder to treat. Based on studies and recommendations, it would be advisable to first treat patients based on their most significant complaint. When an FDA-approved medication for fibromyalgia is being selected, treatment should be tailored to the individual patient.
1. Calandre EP, Rico-Villademoros F, Slim M. An update on pharmacotherapy for the treatment of fibromyalgia. Expert Opin Pharmacother. 2015;16:1347-1368.
2. Dymon TE. Fibromyalgia. In: ACSAP 2015 Book 1—Neurologic and Psychiatric Care. Lenexa, KS: American College of Clinical Pharmacy; 2015:5-18.
3. Theoharides TC, Tsilioni I, Arbetman L, et al. Fibromyalgia syndrome in need of effective treatments. J Pharmacol Exp Ther. 2015;355:255-263.
4. MacLean AJ, Schwartz TL. Tramadol for the treatment of fibromyalgia. Expert Rev Neurother. 2015;15:469-475.
5. Häuser W, Walitt B, Fitzcharles MA, Sommer C. Review of pharmacological therapies in fibromyalgia syndrome. Arthritis Res Ther. 2014;16:201.
6. Lexi-Drugs. Lexicomp [online database]. Hudson, OH: Wolters Kluwer Health, Inc; 2016. http://online.lexi.com. Accessed January 25, 2016.
7. Gold Standard, Inc. Clinical Pharmacology [online database]. Philadelphia, PA: Elsevier; 2016. www.clinicalpharmacology.com. Accessed January 25, 2016.
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